AbstractFew germline genetic variants have been robustly linked with breast cancer outcomes. We conducted trans-ethnic meta genome-wide association study (GWAS) of overall survival (OS) in 3973 breast cancer patients from the Pathways Study, one of the largest prospective breast cancer survivor cohorts. A locus spanning the UACA gene, a key regulator of tumor suppressor Par-4, was associated with OS in patients taking Par-4 dependent chemotherapies, including anthracyclines and anti-HER2 therapy, at a genome-wide significance level ($P = 1.27 \times 10^{ - 9}$ P = 1.27 × 1 0 − 9 ). This association was confirmed in meta-analysis across four independent prospective breast cancer cohorts (combined hazard ratio = 1.84, $P = 1.28 \times 10^{ - 11}$ P = 1.28 × 1 0 − 11 ). Transcriptome-wide association study revealed higher UACA gene expression was significantly associated with worse OS ($P = 4.68 \times 10^{ - 7}$ P = 4.68 × 1 0 − 7 ). Our study identified the UACA locus as a genetic predictor of patient outcome following treatment with anthracyclines and/or anti-HER2 therapy, which may have clinical utility in formulating appropriate treatment strategies for breast cancer patients based on their genetic makeup.